At the time of the strike, Gould owned all the elevated rail lines in New York City, the Western Union telegraph service and the Union Pacific, Missouri Pacific, Missouri Kansas & Texas (M-K-T) railroads. In total, Gould owned almost 12 percent of all railroad track in the U.S.

The strike began when a member of the Knights of Labor in Marshall, Texas was fired for attending a union meeting on company time. The local chapter of the Knights called a strike.

Soon, more than 200,000 workers were on strike in Arkansas, Illinois, Kansas, Missouri and Texas. Although the dismissal of the leadman in Texas had sparked the initial strike, wages, hours and unsafe working conditions motivated most of the strikers.

From the start there were problems. The Brotherhood of Engineers refused to honor the strike, and its members kept working.

Meanwhile, Gould immediately hired strikebreakers to work the railroad, allegedly declaring, "I can hire one half of the working class to kill the other half."

On March 19, 1886, Grand Master Workman Terence V. Powderly of the Knights of Labor met in Kansas City, Missouri with other leaders of the Knights, the governors of Kansas and Missouri, and railroad officials to try to bring an end to the strike. The meeting continued for two days, but the parties were unable to reach an agreement.

After several incidents of 'union violence' occurred, Gould requested military assistance from the governors of the affected states. The governor of Missouri mobilized the state militia; the governor of Texas mobilized both the state militia and the Texas Rangers. The governor of Kansas refused after local officials reported no incidents of violence, despite claims by railway executives that mobs had seized control of trains and rail yards were burning.

The exercise of state police power on behalf of the railways led union members to retaliate. Switching houses were burned, mechanic shops wrecked and trains uncoupled. Shots were fired at a moving train in Missouri. A favorite tactic of the rail workers was to let steam locomotives go cold, forcing the railroad to spend up to six hours slowly reheating the engines for use.

As the violence spread, public opinion turned against the workers. The physical attacks by the Pinkerton agents scared thousands of workers into returning to work.

The strike petered out during the summer of 1886. By September, the strike was over.

The failure of the great Southwest railroad strike represented the first major defeat sustained by the Knights of Labor. When the strike did not draw the support of the engineers and other industrial workers, the Knights' vision of an industrial union withered as well. Internal conflict broke out between various factions within the Knights, paralyzing the union.

The great Southwest railroad strike, the Haymarket riot, and the collapse of the 1887 sugar strikes in Louisiana demoralized the Knights of Labor and energized management. By 1890, membership in the Knights of Labor had plummeted by 90 percent. Employers adopted a model for stamping out strikes that called for holding firm and calling for government troops.

While the collapse of the railroad strike set the American labor movement back, alleged organizational problems within the Knights of Labor also became apparent. This led Samuel Gompers of the cigar makers union, Peter J. McGuire of the carpenters union and others to organize what he considered a more effective labor organization. On December 8, 1886, they and a few other delegates met in Columbus, Ohio, to create the American Federation of Labor.